Abstract
The cerebellar circuits comprise a limited number of neuronal phenotypes embedded in a defined cytoarchitecture and generated according to specific spatio-temporal patterns. The local GABAergic network is composed of several interneuron phenotypes that play essential roles in information processing by modulating the activity of cerebellar cortical inputs and outputs. A major issue in the study of cerebellar development is to understand the mechanisms that underlie the generation of different interneuron classes and regulate their placement in the cerebellar architecture and integration in the cortico-nuclear network. Recent findings indicate that the variety of cerebellar interneurons derives from a single population of multipotent progenitors whose fate choices are determined by instructive environmental information. Such a strategy, which is unique for the cerebellum along the neuraxis, allows great flexibility in the control of the quality and quantity of GABAergic interneurons that are produced, thus facilitating the adaptive shaping of the cerebellar network to specific functional demands.
Similar content being viewed by others
References
Alder J, Cho NK, Hatten ME (1996) Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron 17:389–399
Wingate RJT (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11:82–88
Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48:17–24
Wang VY, Rose MF, Zoghbi H (2005) Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48:31–43
Englund CM, Kowalczyk T, Daza RAM, Dagan A, Lau C, Rose MF et al (2006) Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J Neurosci 26:9184–9195
Fink AJ, Englund C, Daza RAM, Pham D, Lau C, Nivison M et al (2006) Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci 26:3066–3076
Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV et al (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47:201–213
Hoshino M (2006) Molecular machinery governing GABAergic neuron specification in the cerebellum. Cerebellum 5:193–198
Miale IR, Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Expl Neurol 4:277–296
Altman J, Bayer SA (1997) Development of the cerebellar system in relation to its evolution, structure and funtions. CRC, Boca Raton
Sekerkovà G, Ilijic E, Mugnaini E (2004a) Bromodeoxyuridine administered during neurogenesis of the projection neurons causes cerebellar defects in rats. J Comp Neurol 470:221–239
Sekerkovà G, Ilijic E, Mugnaini E (2004b) Time of origin of unipolar brush cells in the rat cerebellum as observed by prenatal bromodeoxyuridine labeling. Neuroscience 127:845–858
Surchev L, Nazwar TA, Weisheit G, Schilling K (2007) Developmental increase of total cell numbers in the murine cerebellum. Cerebellum 6(4):315–320
Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés. Maloine, Paris
Palay SL, Chan-Palay V (1974) Cerebellar cortex. Cytology and organization. Springer, Berlin
Celio MR (1990) Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience 32:375–475
Bastianelli E (2003) Distribution of calcium-binding proteins in the cerebellum. Cerebellum 2:242–262
Weyer A, Schilling K (2003) Developmental and cell type-specific expression of the neuronal marker NeuN in the murine cerebellum. J Neurosci Res 73:400–409
Leto K, Carletti B, Williams IM, Magrassi L, Rossi F (2006) Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 26:11682–11694
Altman J (1972) Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol 145:353–398
Hallonet ME, Teillet MA, Le Douarin NM (1990) A new approach to the development of the cerebellum provided by the quail-chick marker system. Development 108:19–31
Hallonet ME, Le Douarin NM (1993) Tracing neuroepithelial cells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail-chick chimaeras. Eur J Neurosci 5:1145–1155
Gao WQ, Hatten ME (1994) Immortalizing oncogenes subvert the establishement of granule cell identity in developing cerebellum. Development 120:1059–1070
Napieralski JA, Eisenman LM (1993) Developmental analysis of the external granular layer in the meander tail mutant mouse: do cerebellar microneurons have independent progenitors? Dev Dyn 197:244–254
Alvarez Otero R, Sotelo C, Alvarado-Mallart RM (1993) Chick/quail chimeras with partial cerebellar grafts: an analysis of the origin and migration of cerebellar cells. J Comp Neurol 333:597–615
Fujita S, Simada M, Nakanuna T (1966) 3H-thymidine autoradiographic studies on the cell proliferation and differentiation in the external and internal granular layers of the mouse cerebellum. J Comp Neurol 128:191–209
Zhang L, Goldman JE (1996a) Generation of cerebellar interneurons from dividing progenitors in white matter. Neuron 16:47–54
Milosevich A, Goldman JE (2002) Progenitors in the postnatal cerebellar white matter are antigenically heterogeneous. J Comp Neurol 452:192–203
Milosevich A, Goldman JE (2004) Potential of progenitors from postnatal cerebellar neuroepithelium and white matter: lineage specified vs multipotent fate. Mol Cell Neurosci 26:342–353
Mathis L, Bonnerot C, Puelles L, Nicolas JF (1997) Retrospective clonal analysis of the cerebellum using genetic laacZ/lacZ mousemosaics. Development 124:4089–4104
Mathis L, Nicolas J (2003) Progressive restriction of cell fates in relation to neuroepithelial cell mingling in the mouse cerebellum. Dev Biol 258:20–31
Pascual M, Abrasolo I, Mingorance-Le Meur A, Martinez A, Del Rio JA, Wright CVE et al (2007) Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression. Pnas 104:5193–5198
Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41:281–294
Weisheit G, Gliem M, Endl E, Pfeffer PL, Busslinger M, Schilling K (2006) Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur J Neurosci 24:466–478
Altman J, Bayer SA (1978) Prenatal development of the cerebellar system in the rat. I. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J Comp Neurol 179:23–48
Pfeffer PL, Payer B, reim G, di Magliano MP, Busslinger M (2002) The activation and maintenance of Pax2 expression at the mid-hindbrain boundary is controlled by separate enhancers. Development 129:307–318
Yamanaka H, Yanagawa Y, Obata K (2004) Development of stellate and basket cells and their apoptosis in mouse cerebellar cortex. Neurosci Res 50:13–22
Jankovski A, Rossi F, Sotelo C (1996) Neuronal precursors in the postnatal mouse cerebellum are fully committed cells: evidence from heterochronic transplantation. Eur J Neurosci 8:2308–2320
Carletti B, Grimaldi P, Magrassi L, Rossi F (2002) Specification of cerebellar progenitors following heterotopic/heterochronic transplantation to the embryonic CNS in vivo and in vitro. J Neurosci 22:7132–7146
Grimaldi P, Carletti B, Magrassi L, Rossi F (2005) Fate restriction and developmental potential of cerebellar progenitors. Transplantation studies in the developing CNS. Prog Brain Res 148:57–68
Pearson BJ, Doe CQ (2004) Specification of temporal identity in the developing nervous system. Annu Rev Cell Dev Biol 20:619–647
McConnell SK, Kaznovsky CE (1991) Cell cycle dependence of laminar determination in developing neocortex. Science 254:282–285
Bohner AP, Akers RM, McConnell SK (1997) Induction of deep layer cortical neurons in vitro. Development 124:915–923
Desai AR, McConnell SK (2000) Progressive restriction in fate potential by neural progenitors during cerebral cortical development. Development 127:2863–2872
Valcanis H, Tan SS (2003) Layer specification of transplanted interneurons in developing mouse neocortex. J Neurosci 23:5113–5122
Baader SL, Bergmann M, Mertz K, Fox PA, Gerdes J, Oberdick J et al (1999) The differentiation of cerebellar interneurons is independent of their mitotic history. Neurosci 90:1243–1254
Lee A, Kessler JD, Read TA, Kaiser C, Corbeil D, Huttner WB et al (2005) Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci 8:723–729
Klein C, Butt SJ, Machold RP, Johnson JE, Fishell G (2005) Cerebellum- and forebrain-derived stem cells possess intrinsic regional character. Development 132:4497–4508
Pons S, Trejo JL, Martinez-Morales JR, Marti E (2001) Vitronectin regulates sonic hedgehog activity during cerebellum development through CREB phosphorylation. Development 128:1481–1492
Baier C, Baader SL, Jankowski J, Gieselmann V, Schilling K, Rauch U et al (2007) Hyaluronan is organized into fiber-like structures along migratory pathways in the developing mouse cerebellum. Matrix Biology 26:348–358
Gliem M, Weisheit G, Mertz KD, Endl E, Oberdick J, Schilling K (2006) Expression of classical cadherins in the cerebellar anlage: quantitative and functional aspects. Mol Cell Neurosci 33:447–458
Zanjani SH, Selimi F, Vogel MW, Haeberlé AM, Boeuf J, Mariani J et al (2006) Survival of interneurons and parallel fiber synapses in a cerebellar cortex deprived of Purkinje cells: studies in the double mutant mouse Grid2Lc/+ ;Bax(−/−). J Comp Neurol 497:622–635
Guijarro P, Simo S, Pascual M, Albasolo I, Del Rio JA, Soriano E (2006) Netrin1 exerts a chemorepulsive effect on migratine cerebellar interneurons in a Dcc-independent way. Mol Cell Neurosci 33:389–400
Manzano J, Cuadrado M, Morte B, Bernal J (2007) Influence of thyroid hormone and thyroid hormone receptors in the generation of cerebellar gamma-aminobutyric acid-ergic interneurons from precursor cells. Endocrinology 148:5746–5751
Bartolini A, Leto K, Ghidinelli S, Rossi F (2008) The development of cerebellar GABAergic interneurons is regulated by environmental cues. Fens Abstr 4,009.1
Carletti B, Rossi F (2008) Neurogenesis in the cerebellum. Neuroscientist 14:91–100
Lee KJ, Jessell TM (1999) The specification of dorsal cell fates in the vertebrate central nervous system. Annu Rev Neurosci 22:261–294
Glasgow SM, Henke RM, MacDonald RJ, Wright CVE, Johnson JE (2005) Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development 132:5461–5469
Dullin JP, Locker M, Robach M, Henningfeld KA, Parain K, Afelik S et al (2007) Ptf1a triggers GABAergic neuronal cell fates in the retina. BMC Dev Biol 7:110
Hori K, Cholewa-Waclaw J, Nakada Y, Glasgow SM, Masui T, Henke RM et al (2008) A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling. Genes Dev 22:166–178
Helms AW, Jonson JE (2003) Specification of dorsal spinal cord interneurons. Curr Opin Neurobiol 13:42–49
Flames N, Pla R, Gelman DM, Rubenstein JL, Puelles L, Marin O (2007) Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcription codes. J Neurosci 27:9682–9695
Fogarty M, Grist M, Gelman D, Marin O, Pachnis V, Kessaris N (2007) Spatial genetic patterning of the embryonic neuroepithelium generates GABAergic interneuron diversity in the adult cortex. J Neurosci 27:10935–10946
Wonders CP, Taylor L, Welagen J, Mbata IC, Xiang JZ, Anderson SA (2008) A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. Dev Biol 314:127–136
Miyoshi G, Butt SJ, Takebayashi H, Fishell G (2007) Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expression precursors. J Neurosci 27:7786–7798
Rymar VV, Sadikot AF (2007) Laminar fate of cortical GABAergic interneurons is dependent on both birthdate and phenotype. J Comp Neurol 50:369–380
Kelsch W, Mosley CP, Lin C-W, Lois C (2007) Distinct Mammalian Precursors are committed to generate neurons with defined dendtritic projection patterns. PLoS Biol 5:2501–2512
Ninkovic J, Mori T, Gotz M (2007) Distinct modes of neuron addition in adult mouse neurogenesis. J Neurosci 27:10906–10911
Merkle FT, Mirzadeh Z, Alvarez-Buylla A (2007) Mosaic organization of neural stem cells in the adult brain. Science 317:381–384
Young KM, Fogarty M, Kessaris N, Richardson WD (2007) Subventricular zone stem cells are heterogeneous with respect to their origins and neurogenic fates in the adult olfactory bulb. J Neurosci 27:8286–8296
De Marchis S, Bovetti S, Carletti B, Hsieh YC, Garzotto D, Peretto P et al (2007) Generation of distrinct types of periglomerular olfactory bulb interneurons during development and in adult mice: implication for intrinsic properties of the subventricular zone progenitor population. J Neurosci 27:657–664
Bovetti S, Peretto P, Fasolo A, De Marchis S (2007) Spatio-temporal specification of olfactory bulb interneurons. J Mol Histol 38:563–569
Batista-Brito R, Close J, Machold R, Fishell G (2008) The distinct temporal origins of olfactory bulb interneuron subtypes. J Neurosci 28:3966–3975
Rubenstein JLR, Merzenich MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior 2:255–267
Levitt P, Livesey KL, Powell EM (2004) Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders. Trends Neurosci 27:400–406
Levitt P (2005) Disruption of interneuron development. Epilepsia 46:22–28
Neki A, Ohishi H, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1996) Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum. Neuroscience 75:815–826
Watanabe D, Inokawa H, Hashimoto K, Suzuki N, Kano M, Shigemoto R et al (1998) Ablation of cerebellar Golgi cells distrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination. Cell 95:17–27
Singec I, Knoth R, Ditter M, Frotscher M, Volk B (2003) Neurogranin expression by cerebellar neurons in rodents and non-human primates. J Comp Neurol 459:278–289
Simat M, Parpan F, Fritschy J-M (2007) Heterogeneity of glycinergic and GABAergic interneurons in the granule cell layer of mouse cerebellum. J Comp Neurol 500:71–83
Dino MR, Willard FH, Mugnaini E (1999) Distribution of unipolar brush cells and other calretinin immunoreactive components in the mammalian cerebellar cortex. J Neurocytol 28:99–123
Geurts FJ, Timmermans JP, Shigemoto R, De Schutter E (2001) Morphological and neurochemical differentiation of large granular layer interneurons in the adult rat cerebellum. Neuroscience 104:499–512
Ino H (2004) Immunohistochemical characterization of the orphan nuclear receptor RORα in the mouse neurvous system. J Histochem Cytochem 52:311–323
Acknowledgements
This work was supported by grants from Ministero dell’Università e della Ricerca Scientifica e Tecnologica (PRIN, nr 2005055095); Ministero della Salute (Nuove terapie cellulari per le malattie neurodegenerative, nr 533F/G1 to FR & LM), European Community (nr 512039); Compagnia di San Paolo (Neurotransplant Project, 2004.2019–2007.0660), Istituto Superiore di Sanità (Convenzione 530/F-A5 to FR and LM); Regione Piemonte (Proj. A14/05 and 865/2006); University of Turin; Ketty Leto is supported by a “Lagrange Project” PhD fellowship from the Cassa di Risparmio di Torino.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Leto, K., Bartolini, A. & Rossi, F. Development of Cerebellar GABAergic Interneurons: Origin and Shaping of the “Minibrain” Local Connections. Cerebellum 7, 523–529 (2008). https://doi.org/10.1007/s12311-008-0079-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12311-008-0079-z